|Year : 2019 | Volume
| Issue : 4 | Page : 439-445
Does pregabalin reduce the sevoflurane requirement during laparoscopic cholecystectomy?
Eiad A Ramzy, Doaa G Diab, Mohamed El Mahdy
Department of Anaesthesia and Surgical ICU, College of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||18-Jun-2019|
|Date of Acceptance||27-Jun-2019|
|Date of Web Publication||06-Jan-2020|
MD Doaa G Diab
Department of Anaesthesia and Intensive Care, College of Medicine, Mansoura University, Mansoura, 35516
Source of Support: None, Conflict of Interest: None
Background Preoperative administration of pregabalin reduces the end-tidal concentrations of sevoflurane (ET-Sevo) during laparoscopic cholecystectomy with the added benefit of improving the quality of postoperative analgesia.
Patients and methods After ethical approval, 43 patients scheduled for laparoscopic cholecystectomy were randomly allocated to receive placebo or 150 or 300 mg of pregabalin, 1 h before induction. Anaesthesia was maintained with 0.5–1.5 minimum alveolar concentration of sevoflurane, to maintain bispectral index at 50–60, with supplemental fentanyl and vecuronium. Changes in heart rate, mean blood pressure, ET-Sevo, quality of extubation and postoperative sedation scores, morphine consumptions and pain scores were recorded.
Results After induction, compared with placebo and pregabalin 150 mg groups, patients receiving pregabalin 300 mg had smaller increases in heart rate (P<0.01), lower ET-Sevo (−45.5 and −42.9%, respectively) (P<0.001), better quality of extubation (P<0.001), higher sedation scores for first 8 postoperative hours (P<0.001), longer time to the first request of morphine (P<0.001), less morphine consumption (P<0.02) and lower pain scores (P<0.001) for the first 24 h after surgery.
Conclusion Preoperative administration of pregabalin 300 mg is effective in reduction of the ET-Sevo during laparoscopic cholecystectomy without noted significant adverse effects.
Keywords: laparoscopic cholecystectomy, pregabalin, sevoflurane
|How to cite this article:|
Ramzy EA, Diab DG, El Mahdy M. Does pregabalin reduce the sevoflurane requirement during laparoscopic cholecystectomy?. Res Opin Anesth Intensive Care 2019;6:439-45
|How to cite this URL:|
Ramzy EA, Diab DG, El Mahdy M. Does pregabalin reduce the sevoflurane requirement during laparoscopic cholecystectomy?. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2020 Jan 29];6:439-45. Available from: http://www.roaic.eg.net/text.asp?2019/6/4/439/275141
| Introduction|| |
Laparoscopic cholecystectomy is a stressful surgical procedure. Pregabalin is an inhibitory γ-aminobutyric acid to the presynaptic voltage-gated calcium channels . Pregabalin has anticonvulsant , anxiolytic , sleep-modulating , antihyperalgesic , opioid-sparing  and antiallodynic  properties through inhibition of the release of excitatory neurotransmitters such as glutamate, norepinephrine, serotonin, dopamine and substance P. These unique characteristics make pregabalin a useful therapeutic agent for treating neuropathic pain and acute postoperative pain in several models of incisional injury including laparoscopic cholecystectomy . Moreover, the preoperative administration of a single dose of pregabalin 150 mg provides hemodynamic stability during laparoscopic cholecystectomy without prolongation of recovery time .
To the best of the authors’ knowledge, this trial is the first to examine the efficacy of pregabalin in the reduction of end-tidal sevoflurane during laparoscopic cholecystectomy.
The authors of this study hypothesised that the benefits of pregabalin might be extended to reduce sevoflurane requirements during laparoscopic cholecystectomy.
This study aimed to compare the effects of single preoperative doses of pregabalin 150 and 300 mg on the end-tidal sevoflurane concentrations (ET-Sevo) in the patients scheduled for laparoscopic cholecystectomy. Perioperative changes in heart rate (HR) and mean arterial blood pressure (MAP), intraoperative fentanyl consumption, quality of extubation, incidence of intraoperative awareness and recall and postoperative morphine consumption were also determined.
| Patients and methods|| |
The study was approved by Mansoura Institutional Review Board (code number: R/17.08.88), clinical trial registry (NCT 01571804), and after obtaining of informed written consent from all participants, 43 American Society of Anesthesiologists physical status class I and II patients aged 25–55 years, scheduled for elective laparoscopic cholecystectomy under sevoflurane anaesthesia were included in this prospective, randomized, double-blinded and placebo-controlled study, at Mansoura University Hospitals from January to August 2017.
Patients with communication barriers; significant cardiovascular, renal, hepatic, endocrinal, and neuropsychiatric diseases; prolonged P-R interval; pregnancy; nursing; hypersensitivity to pregabalin; and those who were treated by pregabalin, antidepressant, anticonvulsants, opiates or benzodiazepines during the past week were excluded.
An independent investigator who was not involved in the study instructed the patients preoperatively about the use of visual analogue scale (VAS) to assess the severity of postoperative pain (0 mm for no pain and100 mm for worst imaginable pain).
Ninety minutes before surgery, the studied patients were allocated randomly into three groups by drawing sequentially numbered sealed opaque envelopes containing a software-generated randomisation code to receive two identical placebo capsules (placebo group) (n=14), one capsule of pregabalin 150 mg and one placebo capsule (pregabalin 150 mg group) (n=15) or two capsules of pregabalin 150 mg (pregabalin 300 mg group) (n=14). The placebo and pregabalin capsules looked identical. An anaesthesiologist who was blinded to the patient’s randomisation administered the anaesthetic. All staff in the operating room was unaware of the randomisation code.
Patients’ monitoring included three-lead ECG, pulse oximetry, noninvasive blood pressure, bispectral index (BIS), train-of-four stimulation of ulnar nerve and capnography. Anaesthesia technique was standardised for all patients.
Anaesthesia was induced with thiopental sodium 4–5 mg/kg and fentanyl 2 μg/kg to achieve the BIS values of 45–60 and HR and MAP within 20% of their baseline values. Vecuronium 0.1 mg/kg was given to facilitate orotracheal intubation. The lungs were ventilated using an inspired fraction of oxygen (FiO2) of 0.4, and minute ventilation was adjusted to maintain normocapnia (EtCO2 between 35 and 40 mmHg). All patients received intravenous granisetron 1 mg after induction of anaesthesia. Anaesthesia was maintained with the titration of 0.5–1.5 minimum alveolar concentrations of sevoflurane to maintain the BIS values at 50–60 and HR and MAP within 20% of their baseline values. Supplemental fentanyl boluses of 1 μg/kg were administered when the BIS values became lower than 50 whereas HR and MAP values exceeded 20% of their baseline. Intravenous boluses of labetalol 20 mg (maximum dose of 300 mg) was considered for persistent increases in HR and MAP values.
During surgery, CO2 pneumoperitoneum was created and the intra-abdominal insufflation pressure was limited to 12 mmHg. After introduction of the four trocars, the patient was placed in the reverse Trendelenburg position. After desufflation of CO2 pneumoperitoneum, the patient was returned to the horizontal position. All procedures were done by the same expert surgeons using the same surgical technique.
At the end of the surgery, sevoflurane was discontinued, and the residual effect of muscle relaxant was reversed with neostigmine 0.04 μg/kg and atropine 0.02 μg/kg. The trachea was extubated when the patient became oriented, cooperative, able to lift head for more than 5 s and had strong hand grip, train-of-four ratio more than 0.9, tidal volume more than 5 ml/kg, arterial oxygen saturation more than 95%, FiO2 less than 0.5 and an end-tidal CO2 less than 42 mmHg. The quality of tracheal extubation was evaluated using a five-point rating scale: 1, no coughing or straining; 2, very smooth, minimal coughing; 3, moderate coughing; 4, marked coughing or straining; and 5, poor extubation, very uncomfortable . After extubation, the patient was transferred to the postanaesthetic care unit for close observation for 1 h. Postoperative analgesia was provided according to the authors’ institution protocol with 12 h intramuscular diclofenac (75 mg) and 2-mg rescue doses of intravenous morphine when VAS scores were 5 or more.
Primary outcome was the intraoperative changes in the Et-Sevo. Secondary outcome variables included the changes in the haemodynamic parameters (HR and MAP), intraoperative fentanyl supplementations, quality of tracheal extubation, first request and postoperative cumulative morphine consumption, postoperative sedation and pain scores and nausea and vomiting and the incidence of intraoperative awareness and recall.
Another investigator who was unaware of the patient’s group and who was not involved in the patient’s management collected the perioperative data. HR and MAP were recorded before (baseline), 45 min after the administration of the study capsules, every 15 min after intubation until the skin closure and every 15 min for the first hour after extubation. Et-Sevo were recorded every 15 min after intubation until the skin closure. Postoperative pain VAS scores were assessed every 1 h for the first 6 h after surgery and then 2 h for the next 18 postoperative hours. Four-hourly morphine consumptions were recorded. The presence and intensity of perioperative adverse effects including dry mouth, flatulence, hypoglycaemia, dizziness, somnolence, ataxia, vertigo, confusion, incoordination, tremor, dyspnoea, blurred or abnormal vision, sedation (four-point verbal rating scores: 1: awake, 2: drowsy, 3: rousable or 4: deep sleep) and nausea and vomiting (0: no nausea; 1: nausea no vomiting; 2: nausea and vomiting) was reported. The patients were asked about intraoperative awareness and recall on the second postoperative day by asking three simple questions using standard interview ‘What was the last thing you remembered happening before you went to sleep? What is the first thing you remember happening on waking? Did you dream or have any other experiences whilst you were asleep?’ 
Data were tested for normality using the Kolmogorov–Smirnov test. Fisher exact test was used for categorical data. Repeated-measures analysis of variance and post-hoc Bonferroni test were done for continuous data. Kruskal–Wallis one-way analysis of variance and post-hoc pairwise Wilcoxon rank sum t-tests were used for noncontinuous data. Data were expressed as mean (SD), number (%), or median (range). A value of P less than 0.05 was considered to represent statistical significance.
Based upon our pilot study, the changes in ET-Sevo at 15 min after induction were normally distributed with a SD of 0.345%. A priori power analysis indicated that 12 patients in each group would be sufficient to detect a 20% reduction in ET-Sevo at 15 min after induction, with a type I error of 0.0167 (0.05/3 possible comparisons) and a power of 80%. We added 10% more patients to account for patients dropping out during the study.
| Results|| |
A total of 43 patients completed the study: 14 in the placebo group, 15 in the pregabalin 150 mg group and 14 in the pregabalin 300 mg group. Patients’ characteristics are shown in [Table 1].
Compared with the placebo and pregabalin 150 mg groups, the preoperative administration of a single dose of pregabalin 300 mg was associated with significant reduction in the ET-Sevo throughout the intraoperative time points (P<0.001; [Figure 1]).
Baseline changes in HR and MAP were similar among the patients in the three studied groups ([Table 2]).
Compared with the placebo and pregabalin 150 mg groups, patients in the pregabalin 300 mg group had significantly lower HR values throughout the study time points (P<0.01; [Table 2]), less intraoperative supplementary fentanyl (P<0.03; [Table 3]), lower extubation scores (P<0.001; [Table 4]) and higher sedation scores for first 8 postoperative hours (P<0.001; [Table 4]), and longer time to the first request of morphine (P<0.001), less morphine consumptions (P<0.02) and lower pain scores (P<0.001) for the first 24 postoperative hours ([Table 3]). Compared with the placebo group, the pregabalin 150-mg group had significantly less morphine consumptions (P<0.05) for the first 12 h after surgery and lower pain scores for the first 6 h after surgery (P<0.001; [Table 3]). Compared with the placebo group, the pregabalin groups had higher sedation scores for first 8 postoperative hours (P<0.05; [Table 4]).
The incidence of postoperative nausea and vomiting was similar among the three studied groups ([Table 4]). Two patients in the pregabalin 300-mg group developed postoperative somnolence for less than 2 h after surgery. No patient developed intraoperative awareness, recall or pregabalin-related adverse effects such as dry mouth, flatulence, hypoglycaemia, dizziness, ataxia, vertigo, confusion, incoordination, tremor, dyspnoea and blurred or abnormal vision ([Figure 2]).
|Figure 2 Intraoperative changes in end-tidal sevoflurane concentrations (%). Data are presented as mean±SD. P<0.001 compared with the *placebo group and †pregabalin 150 mg group.|
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| Discussion|| |
The main finding in this study was that the administration of a single dose of pregabalin 300 mg before laparoscopic cholecystectomy significantly reduced the ET-Sevo, HR, intraoperative need for fentanyl supplementations and postoperative morphine consumptions and pain scores without reported adverse effects, except for short-lived higher sedation scores.
The BIS is an established monitor for the depth of anaesthesia which is commonly used to guide the anaesthetic requirements. Unfortunately, a recent study by Whitlock et al.  found that BIS was correlated poorly to the end-tidal anaesthetic concentrations, which makes it incapable of finely guiding volatile anaesthetic titration during anaesthetic maintenance. Therefore, this study considered the combined use of BIS and 20% changes in haemodynamics from their baseline values to titrate the anaesthetic requirements.
The reported significant reductions in ET-Sevo and intraoperative fentanyl supplementations in this study after the preoperative administration of pregabalin 300 mg may be attributed to the unique characteristics of pregabalin such as anxiolytic , sleep-modulating , antihyperalgesic , opioid sparing  and antiallodynic  properties. Similarly others  reported less intraoperative analgesic consumption with haemodynamic stability after the administration of a single oral dose of pregabalin 150 mg before laparoscopic cholecystectomy.
The use of pregabalin 300 mg was associated with lower HR values (−10 beat/min) in this study throughout the study time points. Other investigators reported similar statistically lower heart values (−6 beats/min) with the preoperative use of 150 mg of pregabalin compared with the placebo during laparoscopic cholecystectomy .
Unsurprisingly, the preoperative use of pregabalin 150 and 300 mg improved the quality of postoperative analgesia and reduced postoperative morphine consumptions for the first 12 and 24 h after laparoscopic cholecystectomy, respectively. Others reported similar reductions in the postoperative opioid consumptions after lumbar discectomy , laparoscopic sleeve gastrectomy , laparoscopic cholecystectomy ,, and transperitoneal nephrectomy  with the preoperative administration of single doses of 150 and 300 mg of pregabalin. This may be explained by its antihyperalgesic and opioid-sparing effects.Moreover, the preoperative use of pregabalin 300 mg in this study improves the quality of extubation, which may be attributed to the reductions in the ET-Sevo and intraoperative fentanyl consumptions and better quality of postoperative analgesia.
Unfortunately, the use of pregabalin 300 mg before laparoscopic cholecystectomy was associated with unwanted higher postoperative sedation scores for the first 8 postoperative hours which may adversely lengthen the duration of hospitalisation. Similarly, other investigators reported prolonged sedation for 2 h after the preoperative administration of pregabalin 300 mg ,.
Similar to others , this study reported nonstatistical changes in the incidence of postoperative nausea and vomiting after the use of pregabalin before laparoscopic cholecystectomy. In contrast, other investigators , reported significant reduction in the incidence of postoperative nausea and vomiting after the preoperative administration of pregabalin. These contradictory results may be referred to the smaller number of studied population in this study which was not powered to test the incidence of postoperative nausea and vomiting.
This study did not report any incident of intraoperative awareness or recall which may be attributed to the study design which was not powered to study intraoperative explicit memory.
This study has some limitations. First, sedation may have been evident when patients were admitted to the operating room when the sedated patient was admitted to the operative room after receiving of pregabalin, which may have compromised the blinding of the treating anaesthesiologist. Second, the results of this study should be interpreted with caution because the study was not powered to test the efficacy of pregabalin in reduction of morphine consumption or improvement in the quality of extubation.
Further studies are needed to study the effects of preoperative administration of pregabalin on the anaesthetic requirements and hospital length of stay after ambulatory laparoscopic cholecystectomy, which is not approved yet at the authors’ centre.
| Conclusion|| |
This study demonstrated that preoperative administration of pregabalin 300 mg is effective in the reduction of ET-Sevo during laparoscopic cholecystectomy without noted significant adverse effects.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]